Abstract 6023: Selinexor synergizes with temozolomide in preclinical models of glioblastoma independent of MGMT promoter methylation
Authors: Leah Henegar, Hua Chang, Christopher J. Walker, Trinayan Kashyap, Marie Maloof, Feng Wang, Kathleen Martyn, Shira Orr, Sharon Tamir, Michael G. Kauffman, Sharon Shacham, Yosef Landesman
Journal: Cancer Research (2022)

Abstract Background: The alkylating agent temozolomide (TMZ) is widely applied as an effective first line treatment to glioblastoma (GBM), but its effectiveness is substantially reduced by the MGMT O6-methylguanine-DNA methyltransferase that repairs the main cytotoxic methylguanine generated by TMZ. Thus, TMZ is more effective in patients who have GBM with MGMT gene silencing promoter hypermethylation. Selinexor is an oral selective inhibitor of Exportin-1 (XPO1/CRM1) with efficacy in various solid and hematological cancers and clinically approved to treat multiple myeloma and diffuse large B cell lymphoma. Selinexor also crosses the blood brain barrier and demonstrates clinically relevant disease control with manageable and reversible side effects in a phase 2 clinical trial for patients with recurrent GBM as a monotherapy (Lassman 2021 Clin Cancer Res). To evaluate the effects of selinexor and TMZ combination, preclinical studies were performed with GBM cell lines in vitro and in mouse xenograft models in vivo. Methods: Cytotoxic effects of selinexor and TMZ were evaluated with two GBM cell lines LN18 and U87MG. The MGMT promoter is hypermethylated in U87MG cells while unmethylated in LN18 cells. The anti-cancer effects of selinexor (20 mg/kg, PO, once weekly) and TMZ (50 mg/kg, PO, QDX5, week 1 only) were also tested in a mouse xenograft model of U87MG using different dosing schedules (8 mice per treatment group). Results: Synergistic cytotoxic effects of selinexor and TMZ were observed in vitro in both LN18 and U87MG cells, regardless of the methylation status of MGMT promoter. In mouse xenograft models of U87MG, at Day 29 of study, compared with the control group, tumor growth inhibition (TGI) is 64.5% (p=0.0002) for selinexor and 67.2% (p=0.0001) for TMZ. The combination of the two agents completely inhibited tumor growth, with a TGI of 101.9% (p&amp;lt;0.0001) for a concomitant schedule and a TGI of 104.1% (p&amp;lt;0.0001) for a sequential schedule. Conclusion: The selinexor and TMZ combination demonstrated synergistic anti-cancer effects in preclinical GBM models. Previous studies have shown that selinexor treatment reduces DNA damage repair proteins involved in multiple DNA repair pathways, which would provide a mechanism to enhance the cytotoxic effects of TMZ in GBM cells independent of MGMT promoter methylation. This combination is now being investigated in an ongoing GBM clinical trial (XPORT-GBM-029, NCT04421378). Citation Format: Leah Henegar, Hua Chang, Christopher J. Walker, Trinayan Kashyap, Marie Maloof, Feng Wang, Kathleen Martyn, Shira Orr, Sharon Tamir, Michael G. Kauffman, Sharon Shacham, Yosef Landesman. Selinexor synergizes with temozolomide in preclinical models of glioblastoma independent of MGMT promoter methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6023.